Neurodegenerative diseases are characterized by the progressive and relentless loss of neurons. One strategy to prevent or slow down neurodegeneration is to stimulate molecules that have neuroprotective activity. Using tissue culture systems we have demonstrated that FoxG1, a member of the Forkhead family of transcription factors, is necessary for the maintenance of neuronal survival. Furthermore, elevated expression of FoxG1 has strong neuroprotective effects. We propose to extend our studies in vivo and predict that elevated levels of FoxG1 will be also be protective in animal models of neurodegenerative disease. We propose to test this prediction by generating transgenic mice that express elevated levels of FoxG1 selectively in neurons. These mice will be crossed with two different mouse models of neurodegenerative disease and the effect on progression of neuropathology evaluated. The two specific aims of this proposal are - Aim 1: To generate transgenic mice overexpressing wild-type FoxG1, a constitutively-active form of FoxG1, and a dominant-negative form of FoxG1. We will use the mouse prion protein (mPrP) promoter to drive expression of the three forms of FoxG1 in mice. Aim 2: Analysis of the effect of FoxG1 overexpression on the brain and in mouse models of neurodegeneration. We will examine the effect of increasing FoxG1 activity, through expression of WT and CA FoxG1, on neuronal survival in the normal brain. In a second part of this aim we will examine whether elevated FoxG1 activity protects mice against neurodegeneration. We will cross FoxG1-overexpressing transgenic mice with R6/2 mice (a model of HD) and with p25/CDK5 inducible-transgenic mice (a model of AD). The project will result in the development of three new mouse lines expressing wild-type and mutant FoxG1 transgenic mice. FoxG1 transgenic mice do not currently exist. We feel that generating these mice and testing whether elevated FoxG1 can protect against neurodegenerative disease will shed insight into the function of FoxG1 in postmitotic neurons in vivo and could identify it as a target for the development of novel therapeutic strategies for neurodegenerative disorders.